The reason for cancer treatment failures following induction with chemotherapy or radiation therapy is still unclear. Many factors have been implicated in therapeutic resistance, such as upregulation of efflux pumps from multidrug resistance family (MDR) p-glycoprotein and other non-classical MDR proteins (multidrug resistance-associated protein, MRP; lung resistance protein, LRP) have been described in a variety of cancers (Lehnert, M. Anticancer Res 1998; 18:2225-2226; Ringborg, U. and Platz, A. Acta Oncol 1996; 5:76-80; Shea, T. C., Kelley, S. L., and Henner, W. D. Cancer Res 1998; 48:527-533). Unfortunately, many tumors that are intrinsically resistant to chemotherapy, such as the gastrointestinal malignancies, have relatively low levels of expression of the MDR genes. For example, only 23% of primary colorectal tumors express MRP and 65% express p-glycoprotein (Filipits M, Suchomel R W, Dekan G, Stigilbauer W, Haider K, Depisch D, Pirker R. Br. J. Cancer 1997; 75: 208-212). Therefore, resistance to therapeutic agents cannot be explained solely on the basis of activation and up-regulation of known MDR genes. Studies have also shown that genetic mutations responsible for tumorigenesis may also contribute to drug resistance. For example, loss of DNA mismatch repair (MMR) genes found in hereditary non-polyposis colorectal cancer (HNPCC), have been associated with a more rapid emergence of clinical drug resistance (de las Alas M M, S Aebi, D Fink, S B Howell, G Los. J Natl Canc Inst 1997; 89:1537-41; Lin X, Howell S B (1999). Mol Pharmacol 56:390-5). Mutations in the K-ras gene, detected in approximately 40% of adenomatous polyps and adenocarcinomas, are associated with an increased relapse rate, mortality and a poor chemotherapeutic response (Arber N, I. Shapira, J. Ratan et al. Gastroenterology 2000; 118:1045-1050). Genes involved in cell cycle regulation, such as p21 and p27, have been shown to protect tumors from undergoing apoptosis elicited by various anticancer agents (Waldman T, Lengauer C, Kinzler K W, Vogelstein B. Nature 1996, 381:713-716; St. Croix B, Florenes V A, Rak J W, Flanagan M, Bhattacharya N, slingerland J M, Kerbel R S. Nature Med 1996, 2:1204-1210). In addition, cell adhesion molecules, such as E-cadherin, confer resistance to cells when exposed to chemotherapeutic agents (Skoudy A, Llosas M D, Garcia de Herreros A. Biochem J 1996).
The mechanisms involved in therapeutic resistance therefore appear to be very complex. Recent evidence suggests that the selectivity of chemotherapy for the relatively few tumors ever cured by drugs depends, to a large extent, upon their easy susceptibility to undergo apoptosis, i.e., to kill themselves (Makin G, Expert Opin Ther Targets. 2002 6(1):73-84; Johnstone R W, Ruefli A A, Lowe S W, Cell. 2002 108(2):153-64; Kamesaki H, Int J Hematol. 1998 68(1):29-43).
Secreted protein acidic and rich in cystein (SPARC) belongs to a family of extracellular proteins, called matricellular proteins. Since its identification and cloning, the functional role of SPARC remains unclear. Its high evolutionary conservation suggests an important physiological role for this protein (Iruela-Arispe M L, Lane T F, Redmond D, Reilly M, Bolender R P, Kavanagh T J, Sage E H. Mol Biol Cell. 1995 March; 6(3):327-43). Initial studies showed that SPARC is important in bone mineralization (Termine J D, Kleinman H K, Whitson S W, Conn K M, McGarvey M L, Martin G R. Cell. 1981 October; 26(1 Pt 1):99-105). While SPARC is expressed at high levels in bone tissue, it is also distributed widely in other tissues and cell types (Maillard, C., et al., Bone, 13:257-264 (1992)). Its role has been expanded to include tissue remodeling (Latvala T, Puolakkainen P, Vesaluoma M, Tervo T. Exp Eye Res. 1996 November;63(5):579-84; Kelm R J Jr, Swords N A, Orfeo T, Mann K G. J Biol. Chem. 1994 Dec. 2;269(48):30147-53); endothelial cell migration (Hasselaar P, Sage E H. J Cell Biochem. 1992 July;49(3):272-83), morphogenesis (Mason I J, Murphy D, Munke M, Francke U, Elliott R W, Hogan B L. EMBO J. 1986 August; 5(8):1831-7; Strandjord T P, Sage E H, Clark J G. Am J Respir Cell Mol. Biol. 1995 September; 13(3):279-87), and angiogenesis (Kupprion C, Motamed K, Sage E H. J Biol. Chem. 1998 Nov. 6; 273(45):29635-40; Lane T F, Iruela-Arispe M L, Johnson R S, Sage E H. J Cell Biol. 1994 May; 125(4):929-43). SPARC has also been shown to have an antiproliferative effect on endothelial cells, mesangial cells, fibroblasts and smooth muscle cells (Sage E H. Biochem Cell Biol. 1992 July; 70(7):579-92).
Experiments in vitro have also identified SPARC in tumors (Schulz, A., et al., Am. J. Pathol., 132:233-238 (1988); Porter, P. L., et al., J. Histochem. Cytochem., 43:791-800 (1995)). There is conflicting evidence that SPARC can function either as an oncogene, as suggested by studies in melanoma (Ledda M F, Adris S, Bravo A T, Kairiyama C, Bover L, Chernajovsky Y, Mordoh J, Podhajcer O L. Nat Med. 1997 February; 3(2):171-6) or as a tumor suppressor, as demonstrated by its strong inhibition of growth in vJun-ml and v-Src-transformed chicken embryo fibroblasts (Vial E, Castellazzi M. Oncogene. 2000 Mar. 30; 19(14):1772-82). Although the growth inhibitory properties of SPARC have been mainly shown in primary cells, such as endothelial, fibroblast, mesangial and smooth muscle cells, this may also contribute to the role of SPARC in tumorigenesis. SPARC has also been shown to have tumor invasive properties. Variable SPARC expression has been observed in a variety of cancers. Higher levels of expression have been detected in breast cancer (Bellahcene A, Castronovo V. Am J Pathol. 1995 January; 146(1):95-100), esophageal cancer (Porte H, Triboulet J P, Kotelevets L, Carrat F, Prevot S, Nordlinger B, DiGioia Y, Wurtz A, Comoglio P, Gespach C, Chastre E. Clin Cancer Res. 1998 June; 4(6):1375-82), hepatocellular carcinoma (Le Bail B, Faouzi S, Boussarie L, Guirouilh J, Blanc J F, Carles J, Bioulac-Sage P, Balabaud C, Rosenbaum J. J Pathol. 1999 September; 189(1):46-52), and prostate (Thomas R, True L D, Bassuk J A, Lange P H, Vessella R L. Clin Cancer Res 2000; 6:1140-1149). However, conflicting results have been seen with ovarian cancers (Brown T J, Shaw P A, Karp X, Huynh M H, Begley, Ringuette M J. Gynecol Oncol 1999; 75: 25-33; Paley P J, Goff B A, Gown A M, Greer B E, Sage E H. Gynecol Oncol 2000; 78: 336-341; Yiu G K, Chan W Y, Ng S W, Chan P S, Cheung K K, Berkowitz R S, Mok S C. Am J Pathol 2001; 159:609-622), and colorectal cancers (Porte H, Chastre E, Prevot 5, Nordlinger B, Empereur S, Basset P, Chambon P, Gespach C. Int J Cancer 1995; 64: 70-75; Lussier C, Sodek J, Beaulieu J F. J Cell Biochem. 2001;81(3):463-76).
Recently, SPARC has been suggested to be involved in inducing apoptosis of ovarian cancer cells (Yiu G K, Chan W Y, Ng S W, Chan P S, Cheung K K, Berkowitz R S, Mok S C. Am J Pathol 2001; 159:609-622). Yiu et al. (2001, supra) has showed that there was downregulation of SPARC expression following malignant transformation, and that there were anti-proliferative properties of SPARC on both normal ovarian and cancer cells. Yiu et al. (2001, supra) further provided additional evidence that exogenous exposure to SPARC alone was capable of inducing apoptosis in ovarian cancer cells. However, human pathological specimens of tumors with high SPARC expression levels have not been shown to have higher number of apoptotic cells.
WO0202771 discloses a novel hSPARC-h1 polypeptide and its potential applications in tissue remodeling, tissue repair and general modulation of various growth factor activities.
U.S. Pat. No. 6,387,664 provides a SPARC fusion protein obtainable by fusing SPARC to thioredoxin which can be used for basic research in neurobiology and/or for treating various neuropathologies.
U.S. Pat. No. 6,239,326 provides a SPARC-deficient transgenic mouse model for testing drugs in promoting or retarding wound healing and treating or preventing cataracts, diabetes mellitus or osteoporosis.
All references cited herein above and throughout the specification, including patents, patent applications, are hereby incorporated by reference in their entirety.